Regulation of Mitochondrial Dynamics by ERAD ABSTRACT Cells face a complex challenge of balancing protein folding and degradation in the endoplasmic reticulum (ER), a multifunctional organelle that is central to human health. Further, dysregulation of this balance accounts for the pathogenesis of many human diseases. ER-associated degradation (ERAD) is a principal quality-control mechanism used by the cells to target misfolded proteins in the ER for proteasomal degradation in the cytosol. However, the physiological function of distinct mammalian ERAD components remain largely unclear. In the last several years, we have explored the physiological importance of cell type-specific ERAD in normal physiology and disease, and have identified molecular substrates and pathways underpinning ERAD- associated pathophysiology. While ERAD expression is known to be controlled by IRE1a signaling of the UPR, we recently discovered a negative feedback loop in which the Sel1L-Hrd1 protein complex of mammalian ERAD restrains IRE1a signaling and activation under the steady state by targeting IRE1a for proteasomal degradation. This study demonstrates an intimate crosstalk between the two most conserved ER quality- control systems. Surprisingly, our recent data in brown adipocytes reveals that Sel1L-Hrd1 ERAD may regulate mitochondrial dynamics, in part via IRE1a. Sel1L-deficient brown adipocytes exhibit a profound morphological alteration of mitochondria in response to cold exposure, which can be partially rescued upon the deletion of IRE1a. One of the major goals for the next five years is to delineate the molecular mechanism underlying the regulation of mitochondrial dynamics by ERAD by testing the overarching hypothesis that Sel1L-Hrd1 ERAD regulates mitochondrial dynamics and function via IRE1a. We will explore whether and how the ?Sel1L- Hrd1 ERAD-IRE1a? axis of ER quality control machineries exerts control over mitochondrial fission-fusion balance. This study may not only reveal the significance of an ?ERAD-UPR? crosstalk at the core of normal cellular function and physiology, but may also provide exciting insights into the organelle crosstalk, a largely mysterious process. With funding support from NIGMS, we have made great progress towards the understanding of the ERAD- UPR biology in mammals in the past several years. Hence, we are uniquely positioned to lead this project with innovation, passion and dedication to scientific discovery. The R35 grant mechanism will give us the intellectual freedom, time and resources to direct our energy for exploration into discovery and will open up new directions to provide unprecedented insights into the role of ER quality-control machineries in mitochondrial biology.